Process Or The Preparation Of A Gadolinium Contrast Agent

Abstract

The present invention relates to a process for the preparation of a gadolinium chelate compound of formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same. Further, the present invention relates to crystalline forms of the gadolinium chelate of formula (I), to a process for the preparation of said crystalline forms as well as to intermediate compounds in the synthesis of the gadolinium chelate compound of formula (I) and/or its crystalline forms as well as their stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.

1 . A process for the isolation of a compound of general formula (I), 
       
         
           
           
               
               
           
         
         or its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same, said process comprising: 
         providing a mixture comprising a compound of general formula (I), water and at least a first organic solvent, 
         removing water from the mixture, 
         adding a second organic solvent, and 
         isolating the compound of general formula (I). 
       
     
     
         2 . The process according to  claim 1 , wherein the second organic solvent is an alcohol selected from the group consisting of ethanol, n-propanol and iso-propanol, and wherein the process further comprises adding a third organic solvent, wherein the third organic solvent is acetone. 
     
     
         3 . The process according to  claim 2 , wherein the second organic solvent is ethanol. 
     
     
         4 . The process according to  claim 1 , wherein removing water from the mixture comprises removing water from the mixture until the water content of the mixture is between 10% and 20% by weight (w/w). 
     
     
         5 . The process according to  claim 1 , wherein the at least first organic solvent is DMSO. 
     
     
         6 . The process according to  claim 1 , wherein isolating the compound of general formula (I) comprises:
 providing an aqueous mixture comprising the compound of general formula (I),   adding a fourth organic solvent and filtering to obtain a solid,   drying the solid.   
     
     
         7 . The process according to  claim 6 , wherein the fourth organic solvent is ethanol, and wherein drying the solid is carried out at a relative humidity of from 18% to 70%. 
     
     
         8 . The process according to  claim 6 , wherein the fourth organic solvent is ethanol, and wherein drying the solid comprises a first drying at a relative humidity of from 0% to 25% followed by a second drying comprising adjusting the relative humidity until a final value of from 18% to 70% is reached. 
     
     
         9 . A crystalline Form I of a compound of general formula (I) 
       
         
           
           
               
               
           
         
       
       characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8±0.2)°, (9.1±0.2)° and (11.4±0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. 
     
     
         10 . A crystalline Form II of a compound of general formula (I) 
       
         
           
           
               
               
           
         
         characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (10.2±0.2)°, (10.8±0.2)° and (11.3±0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. 
       
     
     
         11 . A process for the preparation of a crystalline Form I of a compound of general formula (I) 
       
         
           
           
               
               
           
         
         said process comprising: 
         providing an aqueous mixture comprising the compound of general formula (I), 
         adding an organic solvent and filtering to obtain a solid, 
         drying the solid at a relative humidity of from 18% to 70%, 
       
       wherein the crystalline Form I is characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8±0.2)°, (9.1±0.2)° and (11.4±0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. 
     
     
         12 . A process for the preparation of a crystalline Form II of a compound of general formula (I) 
       
         
           
           
               
               
           
         
         the process comprising: 
         providing an aqueous mixture comprising the compound of general formula (I), 
         adding an organic solvent and filtering to obtain a solid, 
         drying the solid at a relative humidity of from 0% to 25%, followed by a second drying comprising adjusting the relative humidity until a final value of from 18% to 70% is reached, 
       
       wherein the crystalline Form II is characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (10.2±0.2)°, (10.8±0.2)° and (11.3±0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. 
     
     
         13 . The process according to  claim 11 , wherein the organic solvent is ethanol. 
     
     
         14 . The process according to  claim 12  wherein the organic solvent is ethanol.